Recent accomplishments of our immunotherapy clinical trials include the following: [ ] PHASE 1 TRIAL OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING PD-L1 AND TGF-beta, IN ADVANCED SOLID TUMORS: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a TGFbeta trap. In the 3+3 dose-escalation component of this phase I study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once every 2 weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; in addition, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/ pharmacodynamics, followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include pharmacokinetics, immunogenicity, and best overall response. Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade greater than or equal to 3 treatment-related adverse events occurred in four patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGFbeta1, -beta2, and -beta3 throughout the dosing period at 1 mg/kg. There were signs of efficacy across all dose levels, including one ongoing confirmed complete response (cervical cancer), two durable confirmed partial responses (PR; pancreatic cancer; anal cancer), one near-PR (cervical cancer), and two cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of efficacy are encouraging, and multiple expansion cohorts are ongoing in a range of tumors. [ ] AVELUMAB FOR METASTATIC OR LOCALLY ADVANCED PREVIOUSLY TREATED SOLID TUMORS (JAVELIN SOLID TUMOR): A PHASE 1A, MULTI-COHORT, DOSE-ESCALATION TRIAL. Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumors while assessing biological correlatives for future development. Eighteen patients were analyzed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. We recorded some evidence of clinical activity in various solid tumors, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3.9-4.1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Anti-drug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. [ ] FIRST-IN-HUMAN PHASE I TRIAL OF A TUMOR-TARGETED CYTOKINE (NHS-IL12) IN SUBJECTS WITH METASTATIC SOLID TUMORS: The NHS-IL12 immunocytokine is composed of two IL12 heterodimers fused to the NHS76 antibody. Preclinical studies have shown that this antibody targets IL12 to regions of tumor necrosis by binding histones on free DNA fragments in these areas, resulting in enhanced antitumor activity. The objectives of this phase I study were to determine the maximum tolerated dose (MTD) and pharmacokinetics of NHS-IL12 in subjects with advanced solid tumors. Subjects (n = 59) were treated subcutaneously with NHS-IL12 in a single ascending-dose cohort followed by a multiple ascending-dose cohort (n = 37 with every 4-week dosing). The most frequently observed treatment-related adverse events (TRAE) included decreased circulating lymphocytes, increased liver transaminases, and flu-like symptoms. Of the grade =3 TRAEs, all were transient and only one was symptomatic (hyperhidrosis). The MTD is 16.8 ug/kg. Although no objective tumor responses were observed, 5 subjects had durable stable disease (range, 6-30+ months). NHS-IL12 was well tolerated up to a dose of 16.8 ug/kg, which is the recommended phase II dose. Early clinical immune-related activity warrants further studies, including combination with immune checkpoint inhibitors. [ ] A PHASE 1 DOSE-ESCALATION TRIAL OF BN-CV301, A RECOMBINANT POXVIRAL VACCINE TARGETING MUC-1 AND CEA WITH COSTIMULATORY MOLECULES: BN-CV301 is a poxviral-based vaccine comprised of recombinant (rec.) Modified vaccinia Ankara (MVA-BN-CV301; prime) and rec. fowlpox (FPV-CV301; boost). Like its predecessor PANVAC, BN-CV301 contains transgenes encoding tumor-associated antigens, MUC1 and CEA, as well as costimulatory molecules (B7.1, ICAM-1, LFA-3). PANVAC was re-engineered to make it safer and more antigenic. This open-label, 3+3 design, dose-escalation trial evaluated three dose levels (DL) of MVA-BN-CV301: one, two or four subcutaneous injections of 4x108 infectious units (Inf.U)/0.5 mL on weeks 0 and 4. All patients received FPV-CV301 subcutaneously at 1x109 Inf.U/0.5 mL every 2 weeks for 4 doses, then every 4 weeks. Clinical and immune responses were evaluated. There were no dose limiting toxicities. Twelve patients enrolled on trial (DL1=3, DL2=3, DL3=6). Most side effects were seen with the prime doses and lessened with subsequent boosters. All treatment-related adverse events were temporary, self-limiting, grade 1/2, and included injection site reactions and flu-like symptoms. Antigen-specific T-cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most patients. Single agent BN-CV301 produced a confirmed partial response (PR) in one patient and prolonged stable disease (SD) in multiple patients, most notably in KRAS mutant gastrointestinal tumors. Furthermore, two patients with KRAS mutant colorectal cancer had prolonged SD when treated with an anti-PD-L1 antibody following BN-CV301. The BN-CV301 vaccine can be safely administered to patients with advanced cancer. Further studies of the vaccine in combination with other agents are planned. [ ] PROLONGED COMPLETE RESPONSE IN A METASTATIC BREAST CANCER PATIENT WITH VACCINE AND HERCEPTIN. A 32 year old female with diagnosed with metastatic ER+/PR+/HER2+ breast cancer in 2006, progressed on multiple therapies including herceptin/letrozole and a HER2-peptide vaccine achieved a complete response on PANVAC (poxvirus vaccine containing tumor-associated antigens, MUC1 and CEA, as well as costimulatory molecules (B7.1, ICAM-1, LFA-3) and herceptin 18 months after starting on trial. This response has continued through present day (10 years in complete response). She continues to receive vaccine (now BN-CV301 - the newer, safer version of PANVAC) and herceptin. Her tumor and peripheral immune responses are being evaluated. Germline and somatic sequencing is underway, as well multispectral analysis of her tumor. Peripheral immune responses demonstrate a robust and sustained T-cell response to MUC1, CEA and the cascade antigen, brachyury.